Non-invasive monitoring of neoadjuvant radiation therapy response in soft tissue sarcomas by multiparametric MRI and quantification of circulating tumor DNA-A study protocol.

BACKGROUND: Wide resection remains the cornerstone of localized soft-tissue sarcomas (STS) treatment. Neoadjuvant radiation therapy (NRT) may decrease the risk of local recurrences; however, its effectiveness for different histological STS subtypes has not been systematically investigated. The proposed prospective study evaluates the NRT response in STS using liquid biopsies and the correlation of multiparametric magnetic resonance imaging (mpMRI) with histopathology and immunohistochemistry. METHODS: Patients with localized high-grade STS, who qualify for NRT, are included in this study. LIQUID BIOPSIES: Quantification of circulating tumor DNA (ctDNA) in patient blood samples is performed by targeted next-generation sequencing. Soft-tissue sarcoma subtype-specific panel sequencing in combination with patient-specific exome sequencing allows the detection of individual structural variants and point mutations. Circulating free DNA is isolated from peritherapeutically collected patient plasma samples and ctDNA quantified therein. Identification of breakpoints is carried out using FACTERA. Bioinformatic analysis is performed using samtools, picard, fgbio, and the MIRACUM Pipeline. MPMRI: Combination of conventional MRI sequences with diffusion-weighted imaging, intravoxel-incoherent motion, and dynamic contrast enhancement. Multiparametric MRI is performed before, during, and after NRT. We aim to correlate mpMRI data with the resected specimen's macroscopical, histological, and immunohistochemical findings. RESULTS: Preliminary data support the notion that quantification of ctDNA in combination with tumor mass characterization through co-registration of mpMRI and histopathology can predict NRT response of STS. CLINICAL RELEVANCE: The methods presented in this prospective study are necessary to assess therapy response in heterogeneous tumors and lay the foundation of future patient- and tumor-specific therapy concepts. These methods can be applied to various tumor entities. Thus, the participation and support of a wider group of oncologic surgeons are needed to validate these findings on a larger patient cohort.

Time-Resolved Quantification of Patellofemoral Cartilage Deformation in Response to Loading and Unloading via Dynamic MRI With Prospective Motion Correction.

BACKGROUND: In vivo cartilage deformation has been studied by static magnetic resonance imaging (MRI) with in situ loading, but knowledge about strain dynamics after load onset and release is scarce. PURPOSE: To measure the dynamics of patellofemoral cartilage deformation and recovery in response to in situ loading and unloading by using MRI with prospective motion correction. STUDY TYPE: Prospective. SUBJECTS: Ten healthy male volunteers (age: [31.4 ± 3.2] years). FIELD STRENGTH/SEQUENCE: T1-weighted RF-spoiled 2D gradient-echo sequence with a golden angle radial acquisition scheme, augmented with prospective motion correction, at 3 T. ASSESSMENT: In situ knee loading was realized with a flexion angle of approximately 40° using an MR-compatible pneumatic loading device. The loading paradigm consisted of 2 minutes of unloaded baseline followed by a 5-minute loading bout with 50% body weight and an unloading period of 38 minutes. The cartilage strain was assessed as the mean distance between patellar and femoral bone-cartilage interfaces as a percentage of the initial (pre-load) distance. STATISTICAL TESTS: Wilcoxon signed-rank tests (significance level: P < 0.05), Pearson correlation coefficient (r). RESULTS: The cartilage compression and recovery behavior was characterized by a viscoelastic response. The elastic compression ([-12.5 ± 3.1]%) was significantly larger than the viscous compression ([-7.6 ± 1.5]%) and the elastic recovery ([10.5 ± 2.1]%) was significantly larger than the viscous recovery ([6.1 ± 1.8]%). There was a significant residual offset strain ([-3.6 ± 2.3]%) across the cohort. A significant negative correlation between elastic compression and elastic recovery was observed (r = -0.75). DATA CONCLUSION: The in vivo cartilage compression and recovery time course in response to loading was successfully measured via dynamic MRI with prospective motion correction. The clinical relevance of the strain characteristics needs to be assessed in larger subject and patient cohorts. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

Multiparametric magnetic resonance imaging for radiation therapy response monitoring in soft tissue sarcomas: a histology and MRI co-registration algorithm.

Rationale: To establish a spatially exact co-registration procedure between in vivo multiparametric magnetic resonance imaging (mpMRI) and (immuno)histopathology of soft tissue sarcomas (STS) to identify imaging parameters that reflect radiation therapy response of STS. Methods: The mpMRI-Protocol included diffusion-weighted (DWI), intravoxel-incoherent motion (IVIM), and dynamic contrast-enhancing (DCE) imaging. The resection specimen was embedded in 6.5% agarose after initial fixation in formalin. To ensure identical alignment of histopathological sectioning and in vivo imaging, an ex vivo MRI scan of the specimen was rigidly co-registered with the in vivo mpMRI. The deviating angulation of the specimen to the in vivo location of the tumor was determined. The agarose block was trimmed accordingly. A second ex vivo MRI in a dedicated localizer with a 4 mm grid was performed, which was matched to a custom-built sectioning machine. Microtomy sections were stained with hematoxylin and eosin. Immunohistochemical staining was performed with anti-ALDH1A1 antibodies as a radioresistance and anti-MIB1 antibodies as a proliferation marker. Fusion of the digitized microtomy sections with the in vivo mpMRI was accomplished through nonrigid co-registration to the in vivo mpMRI. Co-registration accuracy was qualitatively assessed by visual assessment and quantitatively evaluated by computing target registration errors (TRE). Results: The study sample comprised nine tumor sections from three STS patients. Visual assessment after nonrigid co-registration showed a strong morphological correlation of the histopathological specimens with ex vivo MRI and in vivo mpMRI after neoadjuvant radiation therapy. Quantitative assessment of the co-registration procedure using TRE analysis of different pairs of pathology and MRI sections revealed highly accurate structural alignment, with a total median TRE of 2.25 mm (histology - ex vivo MRI), 2.22 mm (histology - in vivo mpMRI), and 2.02 mm (ex vivo MRI - in vivo mpMRI). There was no significant difference between TREs of the different pairs of sections or caudal, middle, and cranial tumor parts, respectively. Conclusion: Our initial results show a promising approach to obtaining accurate co-registration between histopathology and in vivo MRI for STS. In a larger cohort of patients, the method established here will enable the prospective identification and validation of in vivo imaging biomarkers for radiation therapy response prediction and monitoring in STS patients via precise molecular and cellular correlation.

Frequency-adjustable magnetic field probes.

PURPOSE: Nuclear Magnetic Resonance field probes provide exciting possibilities for enhancing MR image quality by allowing for calibration of k-space trajectories and/or dynamic measurement of local field changes. The purpose of this study is to design and build field probes, which are easier to manufacture and more flexible to use than existing probes. METHODS: A new manufacturing method is presented based on light-activated resin to encase the coil assembly and the 1H sample. This method allows for realizing field probes with tightly integrated orthogonal coils, whereby the local resonance frequency of protons can be adjusted during the MR experiment, by applying a DC current to the integrated B0 -field modification coil. RESULTS: The apparent field probe position in a gradient echo experiment was shifted within the field of view by changing its Larmor frequency using an integrated micro-coil with 5.5 windings. The measured frequency modulation induced by the B0 -field modification coil was 113 Hz/mA. The probe was tested with currents up to 100 mA. The DC current in the local field modification coil did not introduce visible artifacts in the MR images. Furthermore selective off-resonant excitation of the new field probes at 2 kHz above the main RF frequency was demonstrated. Gradient impulse response functions measured with a traditional and proposed probe show similar gradient imperfections. CONCLUSIONS: The presented approach opens up new possibilities for concurrent field monitoring during MR experiments using standard RF capabilities of clinical scanners.

Molecular MRI in the Earth's Magnetic Field Using Continuous Hyperpolarization of a Biomolecule in Water.

In this work, we illustrate a method to continuously hyperpolarize a biomolecule, nicotinamide, in water using parahydrogen and signal amplification by reversible exchange (SABRE). Building on the preparation procedure described recently by Truong et al. [ J. Phys. Chem. B , 2014 , 118 , 13882 - 13889 ], aqueous solutions of nicotinamide and an Ir-IMes catalyst were prepared for low-field NMR and MRI. The (1)H-polarization was continuously renewed and monitored by NMR experiments at 5.9 mT for more than 1000 s. The polarization achieved corresponds to that induced by a 46 T magnet (P = 1.6 × 10(-4)) or an enhancement of 10(4). The polarization persisted, although reduced, if cell culture medium (DPBS with Ca(2+) and Mg(2+)) or human cells (HL-60) were added, but was no longer observable after the addition of human blood. Using a portable MRI unit, fast (1)H-MRI was enabled by cycling the magnetic field between 5 mT and the Earth's field for hyperpolarization and imaging, respectively. A model describing the underlying spin physics was developed that revealed a polarization pattern depending on both contact time and magnetic field. Furthermore, the model predicts an opposite phase of the dihydrogen and substrate signal after one exchange, which is likely to result in the cancelation of some signal at low field.